Ionizing radiation exposure during childhood is the only well-established environmental risk factor for thyroid cancer, but this exposure cannot explain more than a small fraction of the observed variation in risk. Because thyroid cancer is rare and because thyroid nodules represent an intermediate endpoint related to thyroid cancer risk, we are involved in two projects, in collaboration with DCEGs Radiation Epidemiology Branch, related to thyroid nodulescancer and genetic susceptibility in people exposed to ionizing radiation. The first involves subjects with thyroid nodules who were diagnosed by ultrasound screening in 1998 among 2998 persons who were living near the Semipalatinsk nuclear test site in Kazakhstan when they were children during the period of weapons testing (1949-1960). A total of 909 persons with thyroid nodules were identified. Genomic DNA was obtained from stored Guthrie cards collected at the time of thyroid examination. We are conducting a nested case-control study within the cohort by frequency matching (1:1) those without nodules (controls) to cases by ethnicity (Kazakh or Russian), gender, and age at the time of examination in 5 year strata. We are analyzing 18 single nucleotide polymorphisms (SNPs) within 10 genes using unconditional logistic regression. In addition, we recently added SNPs in RET, its coreceptors, and in TSHR. The second involves subjects in the radiologic technologist cohort study of over 90,000 x-ray technologists. We will evaluate SNPs in DNA damage repair genes, RET, and TSHR in a nested case-control study of the approximately 175 subjects who have been diagnosed with thyroid cancer. Although the radiation exposures are not as high as in the Kazakhstan study of thyroid nodules, detailed work histories and exposure estimates are available for this cohort.